Potentiation of #betalactam #antibiotics and β-lactam/β-lactamase inhibitor combinations against #MDR and #XDR #Pseudomonas aeruginosa using non-ribosomal #tobramycin–cyclam conjugates (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Potentiation of β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin–cyclam conjugates

Temilolu Idowu, Derek Ammeter, Gilbert Arthur, George G Zhanel, Frank Schweizer

Journal of Antimicrobial Chemotherapy, dkz228, https://doi.org/10.1093/jac/dkz228

Published: 28 May 2019

 

Abstract

Objectives

To develop a multifunctional adjuvant molecule that can rescue β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clinical isolates.

Methods

Preparation of adjuvant was guided by structure–activity relationships, following standard protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold dilution assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model.

Results

Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as determined by CLSI susceptibility breakpoints, were attained in several MDR clinical isolates, and time–kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime/avibactam (approved), aztreonam/avibactam (Phase III) and meropenem/avibactam enhances the efficacies of β-lactam/β-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations.

Conclusions

Non-ribosomal tobramycin–cyclam conjugate mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates β-lactam/β-lactamase inhibitors against carbapenem-resistant clinical isolates, highlighting the complexity of resistance to β-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of β-lactam antibiotics.

Topic: antibiotics – pseudomonas aeruginosa – immunologic adjuvants – pharmaceutical adjuvants – aztreonam – ceftazidime – lactams – ribosomes – infection – tobramycin – meropenem – toxic effect – potentiation – avibactam – carbapenem resistance

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Beta-lactams; Pseudomonas aeruginosa; Tobramycin; Aztreonam; Avibactam; Ceftazidime.

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#SME-4-producing #Serratia marcescens from #Argentina belonging to clade 2 of the S. marcescens phylogeny (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

SME-4-producing Serratia marcescens from Argentina belonging to clade 2 of the S. marcescens phylogeny

Laura Dabos, Rafael Patiño-Navarrete, Marcela Nastro, Angela Famiglietti, Philippe Glaser, Carlos H Rodriguez, Thierry Naas

Journal of Antimicrobial Chemotherapy, dkz115, https://doi.org/10.1093/jac/dkz115

Published: 16 April 2019

 

Abstract

Background

SME carbapenemases are increasingly reported, especially from North and South America. Here, we describe an SME-4-producing Serratia marcescens(SME-Sm) clinical isolate from Argentina and compare its genome with other SME-Sm and Sm isolates recovered from public databases.

Methods

Sm isolates were characterized by WGS using Illumina technology, susceptibility testing and MIC determination. Carbapenemase activity was revealed by biochemical tests based on imipenem hydrolysis. A whole-genome phylogeny was estimated for all the Sm isolates retrieved from public databases with kSNP3 and a whole-genome phylogenetic analysis based on non-recombinant core SNPs was inferred for Sm complete genomes and for those encoding any blaSME variants.

Results

Sm163 was resistant to amoxicillin, temocillin, aztreonam and carbapenems, remaining susceptible to extended-spectrum cephalosporins. WGS analysis of Sm163 revealed a genome of 5 139 329 bp and a chromosomally encoded blaSME-4 carbapenemase gene located on a genomic island closely related to SmarGI1-1 of Sm N11-02820. Comparison of the Sm genomes revealed that the 14 SME-Sm isolates possess this genomic island inserted at the same loci, that 13/14 belong to clade 1 and that 11/14 form a well-defined subcluster of cluster I of Sm clade 1, while Sm163 belongs to clade 2, suggesting that an SME-encoding genomic island may have been transferred between isolates from different clades.

Conclusions

To the best of our knowledge this is the first report of an SME-4-encoding Smfrom Argentina. The blaSME-4 gene is located on a SmarGI1-1-like genomic island. The genome of Sm163 belongs to clade 2, unlike all the other SME-Smisolates, which belong to clade 1.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Carbapene; Serratia marcescens; Amoxicillin; Temocillin; Aztreonam; Argentina.

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Activity of #nacubactam (RG6080/OP0595) combinations against #MBL-producing #Enterobacteriaceae (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Activity of nacubactam (RG6080/OP0595) combinations against MBL-producing Enterobacteriaceae

Shazad Mushtaq, Anna Vickers, Neil Woodford, Andreas Haldimann, David M Livermore

Journal of Antimicrobial Chemotherapy, dky522, https://doi.org/10.1093/jac/dky522

Published: 24 December 2018

 

Abstract

Background

Diazabicyclooctanes (DBOs) are promising β-lactamase inhibitors. Some, including nacubactam (OP0595/RG6080), also bind PBP2 and have an enhancer effect, allowing activity against Enterobacteriaceae with MBLs, which DBOs do not inhibit. We tested the activity of nacubactam/β-lactam combinations against MBL-producing Enterobacteriaceae.

Methods

Test panels comprised (i) 210 consecutive Enterobacteriaceae with NDM or VIM MBLs, as referred by UK diagnostic laboratories, and (ii) 99 supplementary MBL-producing Enterobacteriaceae, representing less prevalent phenotypes, species and enzymes. MICs were determined by CLSI agar dilution.

Results

MICs of nacubactam alone were bimodal, clustering at 1–8 mg/L or >32 mg/L; >85% of values for Escherichia coli and Enterobacter spp. fell into the low MIC cluster, whereas Proteeae were universally resistant and the Klebsiella spp. were divided between the two groups. Depending on the prospective breakpoint (4 + 4 or 8 + 4 mg/L), and on whether all isolates were considered or solely the Consecutive Collection, meropenem/nacubactam and cefepime/nacubactam inhibited 80.3%–93.3% of MBL producers, with substantial gains over nacubactam alone. Against the most resistant isolates (comprising 57 organisms with MICs of nacubactam >32 mg/L, cefepime ≥128 mg/L and meropenem ≥128 mg/L), cefepime/nacubactam at 8 + 4 mg/L inhibited 63.2% and meropenem/nacubactam at 8 + 4 mg/L inhibited 43.9%. Aztreonam/nacubactam, incorporating an MBL-stable β-lactam partner, was almost universally active against the MBL producers and, unlike aztreonam/avibactam, had an enhancer effect.

Conclusions

Nacubactam combinations, including those using MBL-labile β-lactams, e.g. meropenem and cefepime, can overcome most MBL-mediated resistance. This behaviour reflects nacubactam’s direct antibacterial and enhancer activity.

Topic: phenotype – cefepime – agar – aztreonam – enterobacter – enterobacteriaceae – klebsiella – laboratory – lactams – diagnosis – enzymes – meropenem – anti-bacterial agents – escherichia coli – enhancer of transcription – dilution technique – dilute (action) – binding (molecular function) – malnutrition-inflammation-cachexia syndrome – avibactam

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Aztreonam; Meropenem; Nacubactam.

——

Clinical #outcomes after combination #treatment with #ceftazidime / #avibactam and #aztreonam for NDM-1/OXA-48/CTX-M-15-producing #Klebsiella pneumoniae infection (J Antimicrob Chemother., summary)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Summary, edited.]

Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection

Evelyn Shaw, Alexander Rombauts, Fe Tubau, Ariadna Padullés, Jordi Càmara, Toni Lozano, Sara Cobo-Sacristán, Núria Sabe, Imma Grau, Raül Rigo-Bonnin, M Angeles Dominguez, Jordi Carratalà

Journal of Antimicrobial Chemotherapy, dkx496, https://doi.org/10.1093/jac/dkx496

Published:  19 December 2017

_____

Sir,

The growing spread of bacteria producing carbapenemases, such as the New Delhi MBL (NDM),1 has created an urgent need to identify effective therapeutic options that can treat serious infections caused by these XDR bacteria. Ceftazidime/avibactam has been successfully used to treat infection caused by carbapenem-resistant Enterobacteriaceae;2,3 however, the combination lacks activity against strains producing NDM. These carbapenemases remain susceptible to aztreonam, although most MBL-producing isolates also harbour ESBLs or other β-lactamases that confer resistance to aztreonam.4 The combination of aztreonam and avibactam has demonstrated potent in vitroactivity against MBL-producing Enterobacteriaceae including those isolates that also carry other β-lactamases.5 However, this combination is currently in clinical development and unavailable for clinical use.

(…)

____

Issue Section:  Research letter

© The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Keywords: Antibiotics; Drugs Resistance; Klebsiella Pneumoniae; NDM1; Ceftazidime; Avibactam; Aztreonam.

——–

#Ceftazidime / #avibactam alone or in combination with #aztreonam against #colistin-resistant and carbapenemase-producing #Klebsiella pneumoniae (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Summary, edited.]

Ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing Klebsiella pneumoniae

Aurélie Jayol, Patrice Nordmann, Laurent Poirel, Véronique Dubois

Journal of Antimicrobial Chemotherapy, dkx393, https://doi.org/10.1093/jac/dkx393

Published: 18 November 2017

 

Summary

Sir,

The spread of carbapenemase-producing Klebsiella pneumoniae is a major public health concern since such isolates are basically resistant to most available antibiotics, including β-lactams, fluoroquinolones and aminoglycosides.1 Infections due to carbapenemase-producing K. pneumoniae are therefore commonly treated with a regimen containing colistin.1 However, acquired resistance to colistin now occurs frequently and has few therapeutic options.2 Outbreaks with colistin-resistant and carbapenemase-producing K. pneumoniae isolates have been reported worldwide2 and mortality rates are high owing to limited treatment options.3

(…)

____

Issue Section: Research letter

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Keywords: Antibiotics; Drugs Resistance; Klebsiella Pneumoniae; Colistin; Carbapenem; Aztreonam; Ceftazidime; Avibactam.

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#Polymyxin Combinations Combat #Escherichia coli Harboring #mcr1 and blaNDM-5: Preparation for a #Postantibiotic Era (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and blaNDM-5: Preparation for a Postantibiotic Era

Zackery P. Bulman a,b, Liang Chen c, Thomas J. Walsh d, Michael J. Satlin d, Yuli Qian e, Jürgen B. Bulitta e, Charles A. Peloquin f, Patricia N. Holden a,b, Roger L. Nation g, Jian Li g, Barry N. Kreiswirth c, Brian T. Tsuji a,b

{a}Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York, USA; {b}School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA; {c}Public Health Research Institute, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA; {d}Weill Cornell Medical College, Cornell University, New York, New York, USA; {e}Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA; {f}Department of Pharmacotherapy and Translational Research, University of Florida, College of Pharmacy, Gainesville, Florida, USA; {g}Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

Gerard D. Wright, Editor

Author Affiliations: McMaster University

Address correspondence to Barry N. Kreiswirth, kreiswba@njms.rutgers.edu, or Brian T. Tsuji, btsuji@buffalo.edu.

B.N.K. and B.T.T. are joint senior authors.

 

ABSTRACT

The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance (mcr-1) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene (blaNDM-5). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance amplification (polymyxin B MIC from 0 to 240 h [MIC0h to MIC240h] of 4 mg/liter), whereas amikacin monotherapy caused regrowth and simultaneous resistance amplification (amikacin MIC0h of 4 mg/liter versus MIC240h of >64 mg/liter). No MCR1_NJ colonies were observed for any of the aztreonam-containing regimens after 72 h. However, HFIM cartridges for both aztreonam monotherapy and the polymyxin B-plus-aztreonam regimen were remarkably turbid, and the presence of long, filamentous MCR1_NJ cells was evident in scanning electron microscopy, suggestive of a nonreplicating persister (NRP) phenotype. In contrast, the 3-drug combination of polymyxin B, aztreonam, and amikacin provided complete eradication (>8-log10 CFU/ml reduction) with suppression of resistance and prevention of NRP formation. This is the first comprehensive pharmacokinetic/pharmacodynamic study to evaluate triple-drug combinations for polymyxin- and carbapenem-resistant E. coli coproducing MCR-1 and NDM-5 and will aid in the preparation for a so-called “postantibiotic” era.

 

IMPORTANCE

A global health crisis may be on the horizon, as the golden era of antibiotics is under serious threat. We recently reported the first case in the United States of a highly resistant, Escherichia coli so-called “superbug” (MCR1_NJ), coharboring two of the most worrying antibiotic resistance genes, encoding mobile colistin resistance (mcr-1) and a New Delhi metallo-β-lactamase (blaNDM-5). Worryingly, the medical community is vulnerable to this emerging bacterial threat because optimal treatment strategies are undefined. Here, we report the activity of an optimized combination using simulated human doses of commercially available antibiotics against MCR1_NJ. A unique triple combination involving a cocktail of polymyxin B, aztreonam, and amikacin eradicated the MCR-1- and NDM-5-producing E. coli. Each antimicrobial agent administered as monotherapy or in double combinations failed to eradicate MCR1_NJ at a high inoculum. To our knowledge, this is the first study to propose 3-drug therapeutic solutions against superbugs coharboring mcr-1 and blaNDM, seeking to prepare clinicians for future occurrences of these pathogens.

KEYWORDS: Enterobacteriaceae – MCR-1 – NDM-5 – amikacin – aztreonam – carbapenem-resistant – polymyxins

 

FOOTNOTES

Citation Bulman ZP, Chen L, Walsh TJ, Satlin MJ, Qian Y, Bulitta JB, Peloquin CA, Holden PN, Nation RL, Li J, Kreiswirth BN, Tsuji BT. 2017. Polymyxin combinations combat Escherichia coli harboring mcr-1 and blaNDM-5: preparation for a postantibiotic era. mBio 8:e00540-17. https://doi.org/10.1128/mBio.00540-17.

Received 4 April 2017 Accepted 19 June 2017 Published 25 July 2017

Copyright © 2017 Bulman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs; Resistance; Colistin; MCR1; NDM5; Polymyxin B; Enterobacteriaceae; Amikacin; Aztreonam; Carbapenem.

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#Repurposing an old #drug: #aztreonam as a new #treatment #strategy for #gonorrhoea (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

ACCEPTED

Repurposing an old drug: aztreonam as a new treatment strategy for gonorrhoea

Benjamin Davido, Aurelien Dinh, Olivia Senard, Ruxandra Calin, Sabrina Makhloufi, Jerome Salomon

J Antimicrob Chemother (2017) dkw589. DOI: https://doi.org/10.1093/jac/dkw589 / Published: 30 January 2017

 

Abstract

Objectives:

To determine whether aztreonam is still an effective drug for the treatment of gonorrhoea.

Methods:

Observational study of patients with gonorrhoea diagnosed by urine multiplex PCR, with a past medical history of allergy to β-lactams or relapse after treatment with a third-generation cephalosporin. Patients received a single 1 g dose of aztreonam in accordance with the manufacturer’s instructions.

Results:

Five patients (four males, one female) were enrolled, comprising two who were allergic to β-lactams and three previously treated with cephalosporins who relapsed. Median age was 38 years (range 23–51). Following treatment with aztreonam all were cured without any adverse event. All the men were free of symptoms, and the woman tested negative for gonorrhoea 1 month after treatment.

Conclusion:

Aztreonam appears to be an effective alternative to cephalosporins in the treatment of uncomplicated gonorrhoea, particularly when patients are suspected of being infected by strains with reduced susceptibility to ceftriaxone or are known to be allergic to penicillin.

Topic: polymerase chain reaction – ceftriaxone – hypersensitivity – cephalosporin – gonococcal infection – aztreonam – lactams – medical history – urine – penicillin allergy – third generation cephalosporin – adverse event

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Neisseria Gonorrhoeae; Aztreonam.

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